The objective of this proposal is to elucidate cellular and biochemical affects of phorbol ester tumor promoters, and related compounds, and to determine the relevance of these effects to the mechanism of tumor promotion. We will test the hypothesis that tumor promoters act by usurping cellular receptors for endogenous growth controlling substances. We will also determine the structural and functional effects of the phorbol esters on membrane lipids and proteins. Effects of phorbol esters on differentiation and gene expression will be examined in cell culture systems and in developing organisms. The protein profile of cells exposed to phorbol esters will be studied to determine the possible roles of proteases, post-translational modifications or altered rates of de novo protein synthesis. The mechanism of interaction between initiating carcinogens, oncogenic viruses and tumor promoters in cell transformation will be studied in fibroblast and epithelial cell culture systems. The specificity of the effects observed in all of these studies, and their relevance to tumor promotion, will be tested through structure-activity correlations, the use of known inhibitors of tumor promotion, and comparative studies in cell culture and epidermal systems. The results should enhance our understanding of the multistep nature of carcinogenesis and provide in vitro systems for detecting tumor promoters in the human environment.